Manufacture of hydroxy-keto compounds having a cyclopentanopolyhydrophenanthrene nucleus



Patented Nov. 28, 1944 2,363,54-sw i MANUFACTURE F HYDROXY-KETO coM- POUNDS HAVING A CYGIl0PENT-ANOPOLY- HYDROPHENANTHREN-E'INUCIJEUS i Rupert,OppenauerQAmSterdam,Netherlandsi 1 vested in the Alienrroperty Custodian 3N0 Drawing. Ap licationMar nes-0, sesame. Y

333,012. n the Nctherlandsiluncfil, 1933;

, 3Claims. (o1. zoo-"39714 1;

This {invention relates to manufacture of hydroxyI-keto compounds having a :cyclopentan'opolyhydrophenanthrene nucleus; and it comprises a process in which an organic compound, containing a cyclopentanopolyhydrophenanthrene nu cleus :and having keto and non-tertiary hydroxy groups attached in positions 3, 20 and zl, is :subjected to the actionof a metalg'alcoholate inJthe presence of an inert solvent, wherebyisomerization and/or dismutation takes place. The inventiont also includes, asia novelcomposition of matter the reaction products of the described process which comprise the isomers and dismutation products of said organic compound ;,;all as more fully hereinafter set forthand .asclaimed.

'This application is a continuation-impart of my copending application, Serial No. 150,758, filed ,clroisyeketo=commond's15 polyhydrophenan hren nucleus 5une28, l937, nowi Patent N0. 12,229,599. ln this prior application-I have describedwanid claimed the same generic invention as thatwhich is disclosed in the present application but theapresent application is directed. to the treatment of:com-' pounds having keto and hydroxy groups in 1 positions 3, and 21 and to the aproductsuresulting fromsaid treatment.

Theraw materials employed in the production of the' '3-keto-1'7-hydroxy compounds having a cyclopentanopolyhydrophenanthrene1 .nucleus,

vents. this treatment: there rare" form dnot onlysythe lower molecular; alcohols :derived; from the :alcoholate employed, but/@150: the alcohol fis of .thesz3i-hydroxy-lfl compoundsathe latter vin "the property, the pre ence ,otanin r solvent, of undergoing isomerization, to? to desired e Wehudroxy, compounds stantial yields which can thenbe recovered-;- in the tormof purezcrysta-lsr ,Ihave toundltha this isomerization areactionl '1 applicable wh 38 3 mg a theoretically possible jor ati least -.on,eziof i ,the droxyl groups toqsbe IDOIIlfiGBd'bY: ontosexchange places a ikc :g ounf isnmeans senate;

least one of: the hydrogtyl groups must i be; teritary. The rhvdr xul a hate group may b attached Koo-one o t erinssi he cycl e wnop-ol hydrophenanthrene nucleus or to a side chain attached tosaid nucleuatoriezcample in that? position. The more important. compoundswhich are operative in; {process are ,those containing at least; one secondary ,hycroiryl group and 1 in which the keto and,-hy,droxyleroup anetattached to different ri-ngs. By methodl have. slicneeded c nv rtin thetlc m ti s-hydmxyare usually the isomeric 3-hYdIOXY-ITPLKEtO'CDmpounds. Thus testosterone, which-is 1&fi3-xk8t0- flfl-hydroxy compound, is usuallywprepared from dehydroandrosterone, which is a:3-hydroxo-r1 7 keto compound. "The 3-ketoel7ehydroxyLoom-f pounds,- such as testosterone and zdihydrotesto sterone for example, not only have agreater ace 3 hadithe disadvantagesthat they are complicated i and that the reactionsemployed do not produce the desired compounds directly, but only via intermediate products, such as the hydroxy-esters,

as described by Ruzicka, Helv, Chim ;Acta 18,

1478 (1935), for example.

I have found that the desired compounds can be produced in a very simple anddirect way by means of an isomerizationreaction in which the raw materials are treated withlower molecular metal alcoholatesin the presence of inert soll'71ket0 compounds ioflthe androsterone and ,gle-

hydroan ms mnevtrpe into the more str ngly active 3-keto-l7rhydroxy; {compounds of the diydmt t tcronetand testosterone type, for, ex

am le-l, i My process can be generally ,app iedto Ithe isomehization-tand ,dismutationof hydrcxy keto;com-

"pounds of the types ,desc'ribedsand inwhichujitcis desired to convert these CQmpol nds intoltheir isomeric ihydroxy-ketotcomnounds, orfintofliheir \polyalcoholic -.or PQly-ketonic,{,derivat"es'; My process :is notlimited ,to,.the iusepf the droxyketo cornpounds vin their pure state ,bu ,crllde or a ural prod cts, such. urine ext acts,

which contain hydroxy keto compounds ,ofthe types idefinedar useful m upro The re.-

, action products and compounds obtained "in this invention are usefiulas Ph rma u icalsi Marious metal ,alcoholaltesfl can, jibe need. .1 1 1 described process among which" there can"be mentioned sodium ethylate, aluminum isopropylate, chloro-magnesium-triphenylcarbinolate and tertiary aluminum butylate. The inert solvent employed should bea substance having no reactive hydroxyl or keto groups. Gasoline, hexane,

benzene and cyclohexane can be mentioned as examples. a i

The reaction of this invention may be effected with such a small quantity of metal alcoholate ple in vacuo, at the beginning of the reaction, During ,the reaction a certain quantity of diol I and dione derivatives is formed and it is possible,

if desired, to adapt my reaction to the produc tion ofthese particular compounds. YThe hydroxy-ketone fraction can be easily separated as the digitonide.

from the diol-dione fraction by knownmethods.

Either of these fractions can be treated again with a metal alcoholate, preferably a tertiary a1- coholate; in accordance with my invention in order toproduce an increased yield of the other fraction. Before effecting this re-treatment, one of the components of the fraction tobere-treated may be separated. Foriexample; it"is possible toseparate testosterone from the hydroxy-ketone fraction by known methods, before re-treatment of the" residue. When re-treating the diol-dione fraction, it is advantageous to have present substantially equal numbers of *hydroxyl and keto groups! Which of the two fractions should be re-treated depends, of course, upon whether'it is desired to recoverone'of the hydroxy-ketone compounds, which are formed in the process, or crystallized diols"and diones." In the treatment of dehydroandr'osterone by my process, for example, it is possible to recover either testosterone or androstendiol and androstehdione, the latter compounds being recovered from the diol-dione fraction and the former from the hydroxy-ketone fraction. If it' is desired to obtain a hydroxyketone compound, the diol-dione fraction maybe subjected to a treatment, this fraction usually being "mixed with the unconverted hydroxyketone which is first separated from the hydroxy- 'ketone fraction. On the other hand if it is desired torecover diol and dione compounds, the hydrox'y-ketone fraction should,be subjected to re-treatment. Since substantially no by-products are formed inmy r'eaction, it is possible by successive "re-treatments to increase the yield of the desired compound or compounds to aption of solvent and time of reaction, or by choice of the fractions to be re-treated or by mixing the fractions to be re-treated in various proportions. I I

- My invention can be described in somewhat greater detail by reference to the following specific example which represents an illustrative embodiment thereof.

Irefiuxed 500 mg. of delta E-pregnene-diol- 3,2l-one-20 with 500 mg. of tertiary aluminumbutylate and 20 cc. of benzene for several. hours in anoil bath. Ether was then addedand dilute sulfuric acidwas added to remove the aluminum. The etheric solution was washed with water, dried and then evaporated,

By treatment with digitonine in alcohol of The compound precipitated by the digitonine was regenerated but was foundto be inactive. The unprecipitated fraction was freed from the excess digitonine and then acetylated at room temperature by treatment with aceticacid anhydride in pyridine. The reaction products were poured into water and dissolved in ether,: the pyridine being removed byrepeated washing of the etheric solution. The solution was then dried and subjected to, evaporation. It was found that 1-2 mg. of the residue, when dis-.

solved in oil, gave a strong cortineactivity in the Everse-de Fremery testv while the starting 'ma-. terial wassubstantiall inactive in this test; j The active component in this product is believed to be the ZI-acetateof delta,4--pregnene-dione13,20

view of this invention. Modifications which fall merization and dismutation' within the scope of the, following claims .will be immediately'evident to those skilledxin this art.

What I claim is: 1. In the isomerization and dismutationof or ganic compounds containing a cyclop'entanopolyabout per cent concentration, approximately half the material was found to be precipitated hydrophenanthrene nucleus and having at least,

one keto group and at least one non-tertiary hye droxyl group attached thereto, the process which comprises treating a 3,21-dihydroxy-26-keto come pound having a cyclopentanopolyhydrophenanthrene nucleus witha small amount of a metal alcoholate in the presence of Van inertv solventflh 2. The process which comprises subjecting'delta 5-pregnene-diol -3,2Lone-20, to the action, of a metal alcoholate in the presence. of aninert sol vent under conditions favoring isomerizationand dismutation.

3. Asa new composition of matter, a mixture of the isomers and dismutation products of delta 5 -p'regnene-diol-3,2l -one-2Q, saidcomposition exdeF-remery test 'and being produced. by subjecting delta 5-pregnene-diol-3,21-one 20 to thetaction of a metal alcoholate in the presence of an inert solvent and under conditions favoring iso- RUPERT QPPE AUERL 

